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Cited by 231Neuroinflammation and Neurodegeneration MechanismsParkinson's Disease Mechanisms and TreatmentsNuclear Receptors and Signaling

The DOI matches its Crossref record; 33 of the 33 references it cites were found in a registry or an index.

Microglial glucocorticoid receptors play a pivotal role in regulating dopaminergic neurodegeneration in parkinsonism

Open access
Ros-Bernal, Francisco, Hunot, Stéphane, Herrero, Maria Trinidad, Parnadeau, Sebastien, Corvol, Jean-Christophe, Lu, Lixia, Alvarez-Fischer, Daniel, Carrillo-de Sauvage, María Angeles, Saurini, Françoise, Coussieu, Christiane, Kinugawa, Kiyoka, Prigent, Annick, Höglinger, Günter, Hamon, Michel, Tronche, François, Hirsch, Etienne C., Vyas, Sheela·2011·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1017820108PMC PMC3080980
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Abstract

Among the pathogenic processes contributing to dopaminergic neuron (DN) death in Parkinson disease (PD), evidence points to non-cell-autonomous mechanisms, particularly chronic inflammation mounted by activated microglia. Yet little is known about endogenous regulatory processes that determine microglial actions in pathological states. We examined the role of glucocorticoid receptors (GRs), activated by glucocorticoids released in response to stress and known to regulate inflammation, in DN survival. Overall GR level was decreased in substantia nigra of PD patients and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated mice. GR changes, specifically in the microglia after MPTP treatment, revealed a rapid augmentation in the number of microglia displaying nuclear localization of GR. Mice with selective inactivation of the GR gene in macrophages/microglia (GR(LysMCre)) but not in DNs (GR(DATCre)) showed increased loss of DNs after MPTP intoxication. This DN loss in GR(LysMCre) mice was not prevented by corticosterone treatment, in contrast to the protection observed in control littermates. Moreover, absence of microglial GRs augmented microglial reactivity and led to their persistent activation. Analysis of inflammatory genes revealed an up-regulation of Toll-like receptors (TLRs) by MPTP treatment, particularly TLR9, the level of which was high in postmortem parkinsonian brains. The regulatory control of GR was reflected by higher expression of proinflammatory genes (e.g., TNF-α) with a concomitant decrease in anti-inflammatory genes (e.g., IL-1R2) in GR(LysMCre) mice. Indeed, in GR(LysMCre) mice, alterations in phosphorylated NF-κB levels indicated its protracted activation. Together, our data indicate that GR is important in curtailing microglial reactivity, and its deregulation in PD could lead to sustained inflammation-mediated DN injury.

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Metadata

Authors
Ros-Bernal, F., Hunot, S., Herrero, M. T., Parnadeau, S., Corvol, J.-C., Lu, L., Alvarez-Fischer, D., Carrillo-de Sauvage, M. A., Saurini, F., Coussieu, C., Kinugawa, K., Prigent, A., Höglinger, G., Hamon, M., Tronche, F., Hirsch, E. C., & Vyas, S.
Affiliations
  • Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) 7224, F-75005 Paris, France;
  • Centre National de la Recherche Scientifique (FR)
  • Clinical and Experimental Neuroscience, Centro de Investigación Biomedica en Red de Enfermedades Neurodegenerativas (CIBERNED), School of Medicine, University of Murcia, 30100 Murcia, Spain;
  • Université Pierre et Marie Curie–Paris 06, F-75252 Paris Cedex 5, France;
  • Inserm (FR)
  • Pitié-Salpêtrière Hospital (FR)
  • Philipps University of Marburg (DE)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2011-04-05
Volume
108
Issue
16
Pages
6632-6637
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.1017820108
PMC
PMC3080980
OpenAlex
W2045465918
Cited by
231
References
33
Citations by year
2026: 7 · 2025: 11 · 2024: 20 · 2023: 7 · 2022: 11 · 2021: 22 · 2020: 10 · 2019: 17 · 2018: 14 · 2017: 15 · 2016: 17 · 2015: 20 · 2014: 16 · 2013: 16 · 2012: 21
FWCI
10.60
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • mediaTUM (Technical University of Munich) (submittedVersion)
Funders
  • Institut National de la Santé et de la Recherche Médicale
  • Fondation de France
  • Centre National de la Recherche Scientifique
  • Ministerio de Ciencia e Innovación
  • Université Pierre et Marie Curie
  • Association France Parkinson
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Receptors and Signaling
Keywords
glucocorticoid receptor, microglia, dopaminergic neuron loss, Parkinson's disease, MPTP-induced neurotoxicity, neuroinflammation, substantia nigra, TLR9, NF-κB signaling, corticosterone, microglial activation, TNF-α, IL1R2, non-cell autonomous neurodegeneration
MeSH terms
Aged, Aged, 80 and over, Animals, Cell Nucleus, Female, Humans, Inflammation, Male, Mice, Transgenic, Parkinson Disease, Receptors, Glucocorticoid, Substantia Nigra, Up-Regulation, Microglia, MPTP Poisoning, Toll-Like Receptors, Mice

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